Stem cell therapies offer enormous hope for solving some of the most tragic illnesses, diseases, and tissue defects world-wide. Mesenchymal stem cells (MSCs), also referred to as connective tissue progenitor cells have immediate clinical utility for treatment of numerous ailments including heart disease due to their convenient isolation, lack of significant immunogenicity, ease of transfection for ex-vivo modification, lack of ethical controversy, and their potential to differentiate into cardiac myocytes. However, a significant barrier to the effective implementation of cell therapies is the inability to target these cells with high efficiency to tissues of interest. This research will build on published and unpublished results generated by the PI and Co-PI (who have been working together during the past 2 years).
The specific aims detailed herein are designed to address the hypothesis that mesenchymal stem cells that are engineered to roll and firmly adhere to vascular endothelim will undergo transmigration. The project will consist of three specific aims. We will assess the ability of MSCs engineered with rolling ligands to firmly adhere to 2D surfaces coated with cell adhesion molecules and we will assess the impact of the cell surface modification on the expression of relevant homing receptors (Aim 1). We will also examine the ability of the modified MSCs to firmly adhere and transmigrate through monolayers of activated endothelial cells (AIM 2). In addition to examining firm adhesion and transmigration under static conditions, and to better mimic the in vivo environment, we will analyze the ability of modified MSCs to firmly adhere and transmigrate under shear stress conditions (Aim 3). It is important to validate our hypothesis in vitro prior to testing the trafficking potential of chemically engineered MSCs in vivo which we hope to explore in a future RO1 proposal. This in vitro work would also help us further establish a suitable in vitro model for interrogating cell trafficking behavior.

Public Health Relevance

In this project we will incorporate adhesion ligands that promote cell rolling, onto the surface of culture expanded mesenchymal stem cells to enhance firm adhesion and transendothelial migration on endothelial monolayers. We will also develop an in vitro model to examine interactions with endothelial cell monolayers that are pre-conditioned under shear stress conditions.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21HL097172-01A1
Application #
7895331
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Lundberg, Martha
Project Start
2010-04-15
Project End
2012-03-31
Budget Start
2010-04-15
Budget End
2011-03-31
Support Year
1
Fiscal Year
2010
Total Cost
$267,536
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Ranganath, Sudhir H; Tong, Zhixiang; Levy, Oren et al. (2016) Controlled Inhibition of the Mesenchymal Stromal Cell Pro-inflammatory Secretome via Microparticle Engineering. Stem Cell Reports 6:926-939
Teo, Grace Sock Leng; Yang, Zijiang; Carman, Christopher V et al. (2015) Intravital imaging of mesenchymal stem cell trafficking and association with platelets and neutrophils. Stem Cells 33:265-77
Sridharan, Rukmani; Karp, Jeffrey M; Zhao, Weian (2014) Bioengineering tools to elucidate and control the fate of transplanted stem cells. Biochem Soc Trans 42:679-87
Choi, Sungyoung; Levy, Oren; Coelho, Mónica B et al. (2014) A cell rolling cytometer reveals the correlation between mesenchymal stem cell dynamic adhesion and differentiation state. Lab Chip 14:161-6
Bose, Suman; Singh, Rishi; Hanewich-Hollatz, Mikhail et al. (2013) Affinity flow fractionation of cells via transient interactions with asymmetric molecular patterns. Sci Rep 3:2329
Teo, Grace S L; Ankrum, James A; Martinelli, Roberta et al. (2012) Mesenchymal stem cells transmigrate between and directly through tumor necrosis factor-?-activated endothelial cells via both leukocyte-like and novel mechanisms. Stem Cells 30:2472-86
Xu, Chenjie; Poh, Yuk Kee C; Roes, Isaac et al. (2012) A portable chemotaxis platform for short and long term analysis. PLoS One 7:e44995
Xu, Chenjie; Miranda-Nieves, David; Ankrum, James A et al. (2012) Tracking mesenchymal stem cells with iron oxide nanoparticle loaded poly(lactide-co-glycolide) microparticles. Nano Lett 12:4131-9
Zhao, Weian; Cui, Cheryl H; Bose, Suman et al. (2012) Bioinspired multivalent DNA network for capture and release of cells. Proc Natl Acad Sci U S A 109:19626-31
Coelho, Mónica Beato; Cabral, Joaquim M S; Karp, Jeffrey M (2012) Intraoperative stem cell therapy. Annu Rev Biomed Eng 14:325-49

Showing the most recent 10 out of 20 publications